Being overweight is a serious public health problem that greatly increases the risk of many diseases such as diabetes, heart disease, respiratory disease, and even some forms of cancer. More than half the population of the U.S. and other countries in the developed world is overweight and often dangerously so. This situation is thought to be the result of a relatively inactive life style and overeating.
In the U.S. some $60 billion dollars are spent annually attempting to lose weight. Most weight-loss strategies are designed to reduce food intake by diet or by increasing physical activity through exercise. Following this prescription, many people lose weight episodically. But even when such regimens are successful, over 90% of the time the lost weight is regained pound for pound. This failure reflects powerful and complex psychological and physiological drives within us that cause us to take in more calories than we need.
Pharmaceutical companies have developed drugs that are designed to reduce the desire for food, that is, to reduce appetite. Though some of these compounds produce weight loss in experimental animals, they have not been found to be effective in humans thus far. The most effective of them, such as the amphetamines, have serious, treatment limiting side-effects.
Recently, invasive surgical approaches have been added to the weight loss armamentarium for the treatment of gravid obesity. In one method, segments of the small bowel are by-passed to reduce the available absorptive surface, thereby reducing the potential for the absorption of the end products of digestion and their contained calories. In another approach, the size of the gastric lumen is reduced surgically. This reduces food intake by decreasing the holding capacity of the stomach and inducing a sense of satiety as the smaller load of food fills the organ. The risks commonly associated with major surgery and the substantial side-effects of such treatments, such as diarrhea, as well as the need to carefully monitor both the size and character of the meal, make them only useful as a last resort for individuals essentially immobilized by their obesity. They are neither practical nor appropriate for millions of patients whose obesity is not as severe, but who are nonetheless substantially and unhealthily overweight.
A safe and effective means to achieve sustained weight loss for the great majority of overweight people still eludes us.
Starch is the major source of calories in the Western diet. Almost 60% of the food eaten in the U.S. and Europe is in the form of carbohydrates, such as starches and simple sugars. Starch is a branched-chain or linear polymer of glucose molecules (FIG. 1). Its digestion in humans and other mammals is the responsibility of an enzyme called α-amylase. Alpha-amylase is a member of family 13 in a group of sixty-two families of enzymes referred to as glycosylhydrolases. Alpha-amylase breaks the α-1,4-glycosidic bond between adjacent glucose molecules in the starch polymer. Through repetitive chemical reactions, α-amylase reduces a starch molecule to smaller and smaller polymers, and eventually reduces it to small glucose polymers, mostly dimers, trimers, and α-limit dextrins (short polymers that contain a branch point such as a α-1,6 glycosidic bond between glucose molecules) (FIG. 1). These small polymers are then reduced to glucose monomers in the small intestines by the enzymes maltase and glucoamylase (FIG. 1). The resulting glucose is absorbed into blood.
In humans, α-amylase is secreted by two glands, the salivary glands and the pancreas. Salivary and pancreatic α-amylase are very similar, though distinct gene products, each with several isoenzymes. The salivary glands release amylase into the mouth, while the pancreas releases it into the small intestine. Each subtype is responsible for about 50% of the starch digestion that occurs in the body.
Inhibitors of various glycosylhydrolases have been known for over 20 years and are found naturally in a variety of plants, fungi, and bacteria. None of these natural inhibitors are specific for α-amylase or particularly effective against this enzyme. There are two types of natural glycosylhydrolase inhibitors: non-competitive and competitive. Competitive inhibitors bind at the active site of the enzyme, and displace the natural substrate. The majority of competitive inhibitors are small sugar monomers or polymers that are chemically similar to the natural substrates they displace. The first generation of these competitive inhibitors are natural products that are found primarily in bacteria and fungi.
The non-competitive inhibitors, on the other hand, do not bind at the active catalytic site of the enzyme and hence do not displace the natural substrate. These non-competitive inhibitors are primarily proteins that are found in various beans and legumes. In humans, acid in the stomach and proteolytic enzymes in the small bowel destroy protein-based inhibitors, rendering them ineffective as inhibitors of glycosylhydrolase enzymes.
Although the natural sugar-based inhibitors do not suffer from this drawback, those that have been discovered thus far are ineffective as inhibitors of α-amylase activity. These natural sugar-based inhibitors are effective against a variety of non-amylase glycosylhydrolases found in the small intestines, such maltase, sucrase, lactase, and glucoamylase.
Glycosylhydrolase inhibitors were originally considered for agriculture uses as natural pesticides to protect plant seeds from insect infestation, but their main commercial use to date has been in the treatment of diabetes. The most well known of these compounds is acarbose, marketed by Bayer as Precose. Acarbose is a tetramer comprised of valienamine (A), 4-amino-4,6-dideoxy-α-D-glucose (B), and maltose (a glucose dimer) (C) sub-units (FIG. 2). Acarbose acts by decreasing the sharp increase in blood glucose concentration seen following the ingestion of a starch or sugar containing meal by patients with type 2 diabetes. This delay in absorption is thought to help prevent the serious side-effects of diabetes produced by highly elevated blood sugar levels.
Although acarbose is safe and almost quantitatively eliminated in feces (that is, it is not readily absorbed by the body), acarbose and similar inhibitors only reduce the rate at which monosaccharides appear in blood. In the end, the whole caloric load is absorbed. This, of course, makes them useless as a means of weight loss. The reason for their ineffectiveness is that even for the enzymes that they most strongly inhibit, such as lactase and glucoamylase, their inhibitory action is insufficient to prevent the breakdown of small sugar polymers into absorbable monosaccharides before they pass out of the small bowel.
In addition, there are also significant side-effects associated with acarbose use. To the extent that acarbose and other similar inhibitors are able to prevent the final stage in starch digestion, they leave relatively high concentrations of undigested substrates, non-absorbable disaccharides and small polymers, in the intestines. This causes the osmotic movement of water into the gut lumen and produces diarrhea in about ⅓ of the patients taking acarbose. Furthermore, a successful inhibitor of this type introduces relatively large quantities of small sugars into the large bowel where they can be metabolized and fermented within bacterial cells. Some of the products of bacterial action, such as lactic acid, are absorbed and their caloric content made available to the patient. Significant amounts gas (CO2) may also be produced, and about ⅓ of the patients taking acarbose complain of gas.